Drug eluting expandable devices

ABSTRACT

The present disclosure relates to drug eluting devices, and their uses. The drug eluting devices can allow for perfusion during deployment. The coatings the may contain bioactive materials which elute once deployed in a patient and can have anti-proliferative, anti-inflammation, or anti-thrombotic effects. Sol gel technology can be used to coat the devices.

FIELD OF THE INVENTION

The present disclosure relates to drug eluting expandable devices usefulfor medical treatments.

BACKGROUND OF THE INVENTION

“Sol-gel” processes are generally used to fabricate porous materialsincluding self-assembled films. A sol is a liquid solution containing acolloid suspension of a material of interest dissolved in an appropriatesolvent. Condensation reactions between the dissolved precursormolecules result in structures (particles, branched chains, linearchains, etc.) forming within the sol. The size, growth rate andmorphology of these structures depend on the kinetics of the reactionswithin the solvent, which in turn are determined by parameters such assolution concentration, amount of water present, the temperature and pHof the solvent, agitation of the solvent and other parameters. Givenenough time, condensation reactions will lead to the aggregation ofgrowing particles or chains until eventually, a gel is formed. The gelcan be visualized as a very large number of cross-linked precursormolecules forming a continuous, macroscopic-scale, solid phase, whichencloses a continuous liquid phase consisting of the remaining solution.In the final steps of the sol-gel process, the enclosed solvent isremoved (generally by drying) and the precursor molecules cross-link (aprocess called aging) resulting in the desired solid.

Sol-gel synthesis of materials offers several advantages over othersynthetic routes. These advantages can include mild processingconditions (low temperature, low pressure, mild pH), inexpensive rawmaterials, no need for vacuum processing or other expensive equipment,and a high level of control over the resulting structure, particularlyas it pertains to porosity. Regarding shape of the final product, thereis essentially no limitation, because the liquid sol can be cast in anyconceivable form before allowed to gel, including monoliths, thin films,fibers and micro- or nano-scale particles.

Porosity of materials produced in sol-gel processes can be controlled ina number of different ways. In the simplest sol-gel process, no specialporogen is added to the sol and the porosity of the final solid isdetermined by the amount of precursor branching or aggregation beforegelling. Average pore size, volume and surface area of porous sol-gelcompositions increase with the size of the precursor molecules prior tothe sol-gel processing.

Porosity can also be manipulated by the presence of additional materialswithin the solvent during the sol-gel process. The incorporation ofsacrificial porogens in the sol (particularly those that can be easilyremoved via heating or other methods), is generally viewed as anefficient method to obtain porous solids when using sol-gel processes.Historically, these efforts were focused upon the fabrication of lowdielectric constant (low-k) insulating films for the microelectronicsindustry. Sacrificial templates can also be used to create pores ininorganic materials formed using sol-gel processes. Sacrificialtemplates are usually amphiphilic molecules (i.e. those havinghydrophilic and hydrophobic properties) capable of self-assembling insolution. These amphiphilic molecules create a highly-ordered structurethat guides the precursor molecules to co-assemble around the structure.Once the precursor molecules co-assemble around the structure, it can beremoved, leaving a negative image void.

Porous materials made using sol-gel processes can be used to deliverbioactive materials. For example, Vallet-Regi et al. (Chem. Mater. 2001,13, 308-311) described charging powdered MCM-41 with ibuprofen. In thiscase, the ibuprofen was loaded into MCM-41 by dissolving the ibuprofenin hexane and adding the MCM-41 compound to the hexane in a powderedform. Munoz et al. (Chem. Mater. 2003, 15 500-503) described anexperiment which demonstrated that ibuprofen could be delivered at adifferent rate from two different formulations of MCM-41, one made usinga 16 carbon surfactant and one made using a 12 carbon surfactant.

Prior to International Patent Application Number PCT/US2004/040270 (PCT'270), which is fully incorporated by reference herein, no referencedescribed an deployable medical device or bioactive material deliverydevice comprising a triblock copolymer template-based sol-gelcomposition formed surface coating with substantially continuouslyinterconnected channels designed to function as a bioactive materialreservoir. Moreover, no reference described a triblock copolymertemplate-based sol-gel composition surface coating with bioactivematerial found within the coating itself before being applied to thesurface of a deployable medical device as well as having substantiallycontinuously interconnected channels that could further function as abioactive material reservoir after being applied to the surface of adeployable medical device. Thus, the invention described in PCT '270provided at least two additional mechanisms through which bioactivematerials could be loaded onto the surface of a deployable medicaldevice.

While the materials and methods described in PCT '270 provided a numberof important benefits (described therein), there is still room forimprovement in the creation of bioactive material carrying materialsmade with sol-gel processes. For instance, better control of bioactivematerial particles during sol-gel processing and after device deploymentcould provide a benefit in allowing more accurate control over theamount of bioactive materials within a particular sol-gel composition aswell as more control over the release rate of bioactive materials from adeployed medical device into the physiological environment after devicedeployment. The present disclosure provides such benefits. Beforedescribing these benefits in more detail, however, background relatingto a further aspect of the present invention is described.

The contents of US 2007/0071789 are herein incorporated by reference inits entirety. US 2007/0071789 describes implantable medical devicesemploying sol-gel composition coatings that function as a bioactivematerial reservoir, and the use of sol-gel composition coatings forimproved adhesion of organic and inorganic substrates. The contents ofU.S. application Ser. No. 10/528,577 also are herein incorporated byreference in its entirety. Ser. No. 10/528,577 describes medical devicesthat release drugs for the selective therapy of specific diseasedtissues or organ parts, characterized in that lipophilic, largelywater-insoluble drugs that bind to any tissue components adhere to thesurfaces of devices that come into contact with the diseased tissue bybeing pressed against it at least for a short time and immediatelyrelease the active agent when in contact with tissue.

WO 2007/092043 describes implantable medical devices employing sol-gelcomposition coatings that functions as a bioactive material reservoir,and the use of sol-gel composition coatings for improved adhesion oforganic and inorganic substrates. U.S. Pat. No. 6,764,690 disclosescontrollably dissolvable silica-xerogels prepared via a sol-gel processand a delivery device including controllably dissolvable silica-xerogelinto which structure a bioactive material is incorporated. U.S. Pat. No.6,544,223 discloses a device for delivering therapeutic agents andmethods of making such a device. The device disclosed includes aninflatable balloon having holes in the walls of the balloon. U.S. Pat.No. 7,115,299 discloses inflatable porous balloons secured at a distalend of a catheter-based device with a composition including a polymerapplied to the outer surface of the balloon.

U.S. Pat. No. 6,524,274 relates to a method for delivering a drug totissue within the body by providing a catheter constructed for insertionin the body which carries a hydrogel. U.S. Pat. No. 7,066,904 relates toa catheter constructed for insertion in the body with a catheter shafthaving an expandable hydrogel-coated porous balloon portion mounted onthe catheter shaft. One of the disadvantages associated with U.S. Pat.No. 6,524,274 and U.S. Pat. No. 7,066,904 is that a separate or custompH solution has to be mixed for inflation of the balloon. This would betoo cumbersome. There also would be different inflation media versus thebody pH or saline.

One challenge in the field of deployable medical devices has beenadhering bioactive materials and bioactive material-containing coatingsto the surfaces of deployable devices so that the bioactive materialswill be released over time once the device is deployed. One approach toadhering bioactive materials to substrates, such as the surface ofdeployable medical devices has been to include the bioactive materialsin polymeric coatings. Polymeric coatings can hold bioactive materialsonto the surface of deployable medical devices, and release thebioactive materials via degradation of the polymer or diffusion intoliquid or tissue (in which case the polymer is non-degradable). Whilepolymeric coatings can be used to adhere bioactive materials to deployedmedical devices, there are problems associated with their use. Oneproblem is that adherence of a polymeric coating to a substantiallydifferent substrate, such as a stent's metallic substrate, is difficultdue to differing characteristics of the materials (such as differingthermal expansion properties). Further, most inorganic solids arecovered with a hydrophilic native surface oxide that is characterized bythe presence of surface hydroxyl groups (M-OH, where M represents anatom of the inorganic material, such as silicon or aluminum). At ambientconditions then, at least a monolayer of adsorbed water molecules coversthe surface, forming hydrogen bonds with these hydroxyl groups.Therefore, due to this water layer, hydrophobic organic polymers cannotspontaneously adhere to the surface of the deployable medical device.Furthermore, even if polymer/surface bonds (including covalent bonds)are formed under dry conditions, those bonds are susceptible tohydrolysis (i.e. breakage) upon exposure to water. This effect isparticularly important in applications where devices or componentscontaining organic/inorganic interfaces must operate in aqueous,corrosive environments such as a human or other animal's body. Thesedifficulties associated with adhering two different material types oftenleads to inadequate bonding between the deployable medical device andthe overlying polymeric coating which can result in the separation ofthe materials over time. Such separation is an exceptionally undesirableproperty in a deployed medical device.

Two different approaches have traditionally been followed to reinforceorganic/inorganic interfaces. The first is the introduction ofcontrolled roughness or porosity on an inorganic surface that inducespolymer mechanical interlocking. The second is chemical modification ofthe inorganic surface via amphiphilic silane coupling agents thatimprove polymer wetting, bonding and interface resistance to water.While these methods provide some benefits, they are not effective in allcircumstances. Thus, there is room for improvement in methods associatedwith adhering inorganic and organic surfaces. Certain sol-gelcomposition embodiments according to the present invention provide suchimprovements.

Paclitaxel coated catheters can have long inflation times. They can alsohave contra-indicated ischemic plots, proximal lesions/left maincoronary artery and a high degree of washout which can be greater than80%. Weeping catheters/balloons can also have long inflation times witha high degree of washout which can be greater than 95%. Dual balloonscan also have long inflation times and be traumatic to a healthy vessel.There is a need for a drug eluting medical device which has anexpandable member coated with sol gel technology, which overcomes theshortcomings of prior art devices.

US 2006/0020243 describes a paclitaxel coated catheter which hasdisadvantages. One is that it has long inflation times. Clinical trialsrequired one minute inflation time. This long inflation time limits thepopulation which can be treated and can lead to ischemic events.Embodiments according to the present disclosure utilize perfusionwhereas US 2006/0020243 does not. Perfusion provides the improvementwhich would reduce ischemic event. Also, the devices according to US2006/0020243 have a high degree of drug washout due to poor coating. Thepresent disclosure relates to devices which overcome the disadvantagesof prior art devices and methods such as disclosed in US 2006/0020243.

SUMMARY OF THE INVENTION

The present disclosure relates to drug eluting expandable devices whichavoids many of the drawbacks of prior art drug eluting devices. Certainembodiments of the presently disclosed devices allow for perfusion whichcan reduce ischemic events during deployment. Also, the present devicesfeature robust adhesion of the bioactive material to expandable memberssuch as balloons. Also, the instant sol gel drug eluting devices allowfor adjustable release rate of the bioactive materials. Anotheradvantage is the minimization of washout. This is especially importantwhen the bioactive materials to be eluted are cytotoxic substances suchas paclitaxel. The presently disclosed sol gel drug eluting devices alsocan have thin sol gel coatings with minimal effect on profile, rewrap,thickness and flexibility.

The present disclosure generally relates to drug eluting expandabledevices, methods of making such devices and their uses. Specifically,the present disclosure provides for drug eluting medical devices havingan expandable member which may be used for treating intravascular orendolumenal diseases or other abnormal conditions. Sol gel technologycan be used to coat the expandable member. The coatings may containbioactive materials which may elute once deployed in a patient and canhave anti-proliferative, anti-inflammation, or anti-thrombotic effects.

One embodiment of the present disclosure relates to a drug elutingdevice comprising an expandable member and at least one coating on theexpandable member comprising at least one layer, wherein the at leastone layer of the at least one coating comprises an adjustable matrixcomposition comprising a sol gel material and a bioactive material. Inanother embodiment, the expandable member is a balloon or a basket. Inanother embodiment, the balloon is a cutting balloon. In anotherembodiment the basket comprises a material including, but not limitedto, shape memory metal, shape memory metal alloy, or a superelasticmaterial. In one embodiment, the material is nickel titanium. The basketcan be self-expanding or manually expanding. In an embodiment, thebasket comprises a metal, polymer, ceramic, or other blends orcombinations thereof. In another embodiment, the expandable member is inassociation with a fixed wire system.

In one embodiment, the bioactive material comprises at least one of ananti-restenotic agent, an anti-inflammatory agent, an HMG-CoA reductaseinhibitor, an antimicrobial agent, an antineoplastic agent, anangiogenic agent, an anti-angiogenic agent, a thrombolytic agent, anantihypertensive agent, an anti-arrhythmic agent, a calcium channelblocker, a cholesterol-lowering agent, a psychoactive agent, ananti-depressive agent, an anti-seizure agent, a contraceptive, ananalgesic, a bone growth factor, a bone remodeling factor, aneurotransmitter, a nucleic acid, an opiate antagonist; a statinincluding, but not limited to cervistatin; paclitaxel; and combinationsthereof.

In one embodiment, the coating comprises two or more layers, each layercomprising an adjustable matrix composition and a bioactive material.The at least one layer may comprise a sol gel material. In anotherembodiment, the two or more layers are different from each other.

In another embodiment, the sol-gel material comprises at least one of anorganic oxide, inorganic oxide, an organically modified silane, and ahybrid oxide comprising an organically modified silane and an organicoxide or inorganic oxide. The inorganic oxides may comprise at least oneof an oxide of silicon, an oxide of titanium, and an oxide of aluminum.In one embodiment, the organically modified silane has the formula(R²)₃—SiR¹, wherein R¹ is independently selected from substituted alkyl,substituted alkenyl, substituted alkynyl, substituted aralkyl,substituted heteroaryl, and substituted alkoxy with the proviso that R¹contains a hydroxyl or amino group, or a functional group that can betransformed to a radical that contains a hydroxyl or amino group;wherein R² is independently selected from halo, optionally substitutedalkoxy, optionally substituted aryloxy, optionally substituted silyloxy,or optionally substituted alkyl with the proviso that all three R²substituents are not simultaneously substituted alkyl.

In another embodiment, the organically modified silane is selected fromthe group consisting of Tetraethoxysilane, Tetramethoxysilane,Methyltriethoxysilane, Methyltrimethoxysilane, ethyltriethoxysilane,ethyltrimethoxysilane, Tetrapropylorthosilicate, Phenyltriethoxysilane,Phenyltrimethoxysilane, Isobutyltriethoxysilane,Isobutyltrimethoxysilane, Diphenyldiethoxysilane,Diphenyldimethoxysilane, Dimethyl(diethoxy)silane,Dimethyl(dimethoxy)silane, Propyltrimethoxysilane,Propyltriethoxysilane, 3-aminopropyltriethoxysilane (AES),3-aminopropyltrimethoxysilane, (3-Glycidoxypropyl)trimethoxysilane,(3-Glycidoxypropyl) triethoxysilane, Hydroxymethyltriethoxysilane,Hydroxymethyltrimethoxysilane,3-(hydroxyl(polyethyleneoxy)propyl)-heptamethyltrisiloxane,N-(2′-aminoacyl)-3-aminopropyltriethoxysilane,3-Gluconamidopropylsiloxane, 3-methacryloxypropyl-trimethoxysilane,3-methacryloxypropyltriethoxysilane, Vinyltrimethoxysilane,Vinyltriethoxysilane, N-β-aminoethyl-γ-aminopropyltrimethoxysilane,N-β-aminoethyl-γ-aminopropylmethyldimethoxysilane,N-methyl-γ-aminopropylmethyldiethoxysilane,Acetoxypropyltrimethoxysilane, Hydridotrimethylsilane,Hydridotriethylsilane, Chloromethyltrimethoxysilane,Chloromethyltriethoxysilane, Cyclohexyltrimethoxysilane,3-(2-aminoethylamino)propyltrimethoxysilane (EDAS),3-(2-aminoethylamino) propyltriethoxysilane (EDAES), Fluoroalkylsilanes,Diethoxymethylvinylsilane, Diethoxymethylphenylsilane,[(N,N-diethylamino)propyl]trimethoxysilane,Anilinomethyltriethoxysilane, and Anilinomethyltrimethoxysilane.

In another embodiment, the adjustable matrix composition comprises aninorganic oxide and an agent that modifies a characteristic of theinorganic oxide selected from the group consisting of hydrophobicity,charge, biocompatibility, mechanical properties, bioactive materialaffinity, storage capacity, and combinations thereof.

In another embodiment, the expandable member comprises a porous ornon-porous material. In another embodiment, the expandable membercomprises a polymer including, but not limited to, polyamide,polyolefin, polyethylene, polyester, polyurethane, elastomer,thermoplastic elastormer, nylon elastomer, nylon, nylon blends,copolyamide block ether, polyether block amides (PEBAX), polyethyleneterephthalate (PET), polytetrafluoroethylene (PTFE), expandedpolytetrafluoroethylene (ePTFE), latex, or silicone; or blends orcombinations thereof.

In another embodiment, the adjustable matrix composition is adjusted toprovide a specific release rate of said bioactive material.

In another embodiment, the coating is non-uniform. The coating can coveronly a portion of the device including, but not limited to, theabluminal portion, just the luminal portion, the proximal portion, thedistal portion, and/or the central portion. In another embodiment thecoating is deposited in a gradient over the length of the device. Inanother embodiment, the coating is in the form of dots or stripes orother non-contiguous pattern.

Another embodiment of the present disclosure relates to a medical systemcomprising a stent and a drug eluting device comprising an expandablemember and at least one coating on said expandable member comprising atleast one layer, wherein said at least one layer of said at least onecoating comprises an adjustable matrix composition comprising a sol gelmaterial and a bioactive material. In one embodiment, the stent is abare metal stent or a drug eluting stent. In another embodiment, thesystem further comprises a delivery catheter. In one embodiment, thedrug eluting stent contains the same bioactive material as that of thedrug eluting device. In another embodiment, the drug eluting stentcontains a different bioactive material from that of the drug elutingdevice.

Another embodiment of the present disclosure relates to a drug elutingdevice comprising a balloon and at least one coating on the ballooncomprising at least one layer, wherein the at least one layer of the atleast one coating comprises a bioactive material, wherein the deviceallows for perfusion during deployment. In one embodiment, the coatingfurther comprises a contrast media. In another embodiment, the coatingfurther comprises a sol gel material. In another embodiment, the coatingis non-uniform. In another embodiment, the coating is in the form ofdots or stripes or other non-contiguous pattern.

In another embodiment, the drug eluting device further comprises amultilumen tubular member comprising two or more lumens, the multilumentubular member comprising a proximal end and a distal end extendingthrough a balloon cavity defined by the balloon. In one embodiment, themultilumen tubular member is a bilumen tubular member comprising atleast one side opening arranged in the bilumen tubular member locatedboth distal and proximal of the balloon and in fluid communication withone another via a first lumen in the bilumen tubular member, the firstlumen extending from the proximal end of the bilumen tubular memberthrough the tubular member to an end hole distal of the balloon; and thesecond lumen is provided for receiving a pressure fluid for inflatingthe balloon.

In another embodiment, the drug eluting device further comprises anaxially elongate catheter shaft, constructed and arranged for insertioninto a distal body lumen, said catheter shaft having an inflationconduit extending axially therethrough; the balloon secured to saidcatheter shaft, the balloon in fluid communication with the inflationconduit and outwardly radially expandable to a preselected configurationin response to inflation thereof. In one embodiment, the balloon ismulti-lobed.

In another embodiment, the drug eluting device further comprises aninflatable member having generally a helically coiled portion, thehelically coiled portion being inflatable from a deflated configurationto an inflated, configuration defining a generally open lumen.

Another embodiment of the present disclosure relates to a method oftreating stenosis or restenosis or in-stent restenosis comprisingdeploying in a subject a drug eluting device comprising an expandablemember and least one coating on the expandable member comprising atleast one layer, wherein the at least one layer of the at least onecoating comprises an adjustable matrix composition comprising a sol gelmaterial and a bioactive material. In another embodiment, the deviceallows for perfusion during deployment.

Another embodiment of the present disclosure relates to a method oftreating stenosis or restenosis or in-stent restenosis comprisingdeploying in a subject a drug eluting device comprising an expandablemember and at least one coating on the device comprising at least onelayer, wherein the at least one layer of the at least one coatingcomprises a bioactive material and a contrast media, wherein the deviceallows for perfusion during deployment. In another embodiment, theexpandable member is a balloon and the at least one coating is depositedon and adhered to the balloon.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a drug eluting medical device having an expandable memberin the compressed state which can be self or manually expanded.

FIG. 2 depicts a drug eluting medical device having expandable ribs intheir expanded state.

FIG. 3 depicts a drug eluting medical device having expandable ribswhich are self-expanding.

FIG. 4 depicts a drug eluting medical device with twelve expandable ribsin their expanded state.

FIG. 5 depicts a drug eluting medical device with a balloon having acoating on its surface.

FIG. 6 depicts another drug eluting medical device with a balloon havinga coating on its working length.

FIG. 7 depicts a drug eluting medical device having an expandable memberwhich allows for perfusion.

FIG. 8 depicts a drug eluting medical device having an expandable memberin association with a fixed wire system.

FIGS. 9A-9D depict substrates with coatings.

FIGS. 10A and 10B depict substrates with coatings having non-uniformlayers.

FIGS. 11A and 11B show scanning electron microscope (SEM) images ofpaclitaxel sol-gel sprayed balloon.

FIG. 12 is an optical image of an expanded balloon with a cerivastatincontaining sol-gel matrix.

FIG. 13 is a scanning electron microscope (SEM) image of an expandedballoon with a cerivastatin containing sol-gel matrix.

FIG. 14 is a drug elution curve for an expanded balloon with apaclitaxel containing sol-gel matrix.

FIG. 15 is a drug elution curve for an expanded balloon with acerivastatin containing sol-gel matrix.

FIG. 16 is another drug elution curve for an expanded balloon with apaclitaxel containing sol-gel matrix.

FIG. 17 is another drug elution curve for an expanded balloon with acerivastatin containing sol-gel matrix.

DETAILED DESCRIPTION OF THE INVENTION

One embodiment of the present disclosure relates to a drug elutingdevice comprising an expandable member and at least one coating on theexpandable member comprising at least one layer, wherein the at leastone layer of the at least one coating comprises an adjustable matrixcomposition comprising a sol gel material and a bioactive material.

As used herein adjustable matrix refers to an admixture that can beoptimized to control retention time on an expandable member's surface aswell as the bioactive agent dose delivered to a treatment site.

A sol gel material is defined herein broadly to cover the product of asol-gel process. This typically involves preparation of a sol, gelationof the sol and removal of the solvent. The sol may be produced frominorganic or organic precursors (e.g. nitrates or alkoxides) and mayconsist of dense oxide particles or polymeric clusters. A sol is definedas a colloidal suspension of solid particles in a liquid. There can beparticulate sols and polymeric sols: the difference can be defined interms of size. Particulate sols contain dense oxide particle typicallyabout 1 nm in size. Polymeric sols generally contain long, hairy,branched suspensions of particles. Any precursor consisting of a metalor metalloid element surrounded by a set of ligands, which includesalkoxides, can be used to prepare a colloidal system. This colloidalsystem can then be used to form a gel in accordance with the presentdisclosure. A gel herein is defined as a substance that contains acontinuous solid skeleton enclosing a continuous liquid phase.

The sol gel process typically involves the manufacture of inorganicmatrices or ceramics through the formation of a sol or suspension insolution. Hydrolysis and condensation of appropriate precursors(typically metal alkoxides or metal chlorides) leads to the formation ofcolloidal or polymeric gels which extend throughout the liquid (therebyentrapping the liquid). Hence, condensation drives the conversionprocess from sol to gel such that a continuous, globally connected solidpolymeric matrix is produced and a wet gel is formed. Polycondensationwithin a silicon based sol is possible due to the hydrolyticsusceptibility of Si—O—Si based polymers. The labile nature of this bondfuels the growth of polymeric networks which then form gels which canthen in turn form a porous solid material when the liquid is removed andthe material is subsequently dried. ‘Aging’ or perhaps additional hightemperature drying can push the condensation process even further suchthat the material may shrink or its surface chemistry may change or itspore size distribution may shift.

In one embodiment, the sol gel material may comprise at least one of anorganic oxide, an inorganic oxide, an organically modified silane, and ahybrid oxide comprising an organically modified silane and an inorganicoxide. In another embodiment, the inorganic oxide comprises at least oneof an oxide of silicon, an oxide of titanium, and an oxide of aluminum.

The term “organically modified” refers to compounds that contain atleast one organic (carbon-based) ligand (in one embodiment a directmetal-carbon (or semiconductor-carbon) bond). The term “organicallymodified silane” refers to a compound that contains at least onenon-hydrolysable carbon-based ligand bonded to silicon. This class ofcompounds is also referred to as ORMOSILs, silane coupling agents,silane couplers, silane adhesion promoters, or simply silanes. Thesecompounds represent a wide variety of compounds because thenon-hydrolysable ligand(s) can be any conceivable organic group(s)synthesized according to the principles of organic chemistry.Non-limiting examples include alkylsilanes (such as, but not limited to,methyltrimethoxysilane, methyltriethoxysilane, dimethyldiethoxysilane,trimethylethoxysilane, vinyltrimethoxysilane, vinyltriethoxysilane,ethyltriethoxysilane, isopropyltriethoxysilane, butyltriethoxysilane,octyltriethoxysilane, dodecyltriethoxysilane, octadecyltriethoxysilane,etc), aryl-functional silanes (e.g. phenyltriethoxysilane, etc.),aminosilanes (e.g. aminopropyltriethoxysilane,aminophenyltrimethoxysilane, aminopropyltrimethoxysilane, etc.),acrylate- and methacrylate-functional silanes (e.g.acryloxypropyltrimethoxysilane, ect), carboxylate, phosphonate, ester,sulfonate, isocyanate, and epoxy functional silanes.

It is important to realize that these compounds still containhydrolysable groups that enable them to undergo hydrolysis/condensationreactions of sol-gel processes. Therefore, each of them or anycombination of two or more of them can be used as sol-gel precursors, orthey can be used in combination with a fully hydrolysable sol-gelprecursor, such as tetraethoxy silane (TEOS) or titanium isopropoxide.The sol-gel composition thus obtained will not be a stoichiometricinorganic oxide. Instead it will be a hybrid sol-gel material that willexhibit bulk chemical, mechanical, physical and other propertiescharacteristic of the particular combination of constituent components.

Exemplary organically modified silanes that can be particularly usefulin this aspect include silane having the formula (R²)₃—SiR¹, wherein R¹is independently selected from substituted alkyl, substituted alkenyl,substituted alkynyl, substituted aralkyl, substituted heteroaryl, andsubstituted alkoxy with the proviso that R¹ contains a hydroxyl or aminogroup, or a functional group that can be transformed to a radical thatcontains a hydroxyl or amino group; wherein R² is independently selectedfrom halo, optionally substituted alkoxy, optionally substitutedaryloxy, optionally substituted silyloxy, or optionally substitutedalkyl with the proviso that all three R² substituents are notsimultaneously substituted alkyl. Alternatively, exemplary organicallymodified silanes may include Tetraethoxysilane, Tetramethoxysilane,Methyltriethoxysilane, Methyltrimethoxysilane, ethyltriethoxysilane,ethyltrimethoxysilane, Tetrapropylorthosilicate, Phenyltriethoxysilane,Phenyltrimethoxysilane, Isobutyltriethoxysilane,Isobutyltrimethoxysilane, Diphenyldiethoxysilane,Diphenyldimethoxysilane, Dimethyl(diethoxy)silane,Dimethyl(dimethoxy)silane, Propyltrimethoxysilane,Propyltriethoxysilane, 3-aminopropyltriethoxysilane (AES),3-aminopropyltrimethoxysilane, (3-Glycidoxypropyl)trimethoxysilane,(3-Glycidoxypropyl)triethoxysilane, Hydroxymethyltriethoxysilane,Hydroxymethyltrimethoxysilane,3-(hydroxyl(polyethyleneoxy)propyl)-heptamethyltrisiloxane,N-(2′-aminoacyl)-3-aminopropyltriethoxysilane,3-Gluconamidopropylsiloxane, 3-methacryloxypropyltrimethoxysilane,3-methacryloxypropyltriethoxysilane, Vinyltrimethoxysilane,Vinyltriethoxysilane, N-β-aminoethyl-γ-aminopropyltnmethoxysilane,N-β-aminoethyl-γ-aminopropylmethyldimethoxysilane,N-methyl-γ-aminopropylmethyldiethoxysilane,Acetoxypropyltrimethoxysilane, Hydridotrimethylsilane,Hydridotriethylsilane, Chloromethyltrimethoxysilane,Chloromethyltriethoxysilane, Cyclohexyltrimethoxysilane,3-(2-aminoethylamino)propyltrimethoxysilane (EDAS),3-(2-aminoethylamino)propyltriethoxysilane (EDAES), Fluoroalkylsilanes,Diethoxymethylvinylsilane, Diethoxymethylphenylsilane,[(N,N-diethylamino)propyl]trimethoxysilane,Anilinomethyltriethoxysilane, and Anilinomethyltrimethoxysilane

In another embodiment, the adjustable matrix composition can comprise aninorganic oxide and an agent that modifies a characteristic of theinorganic oxide selected from the group consisting of hydrophobicity,charge, biocompatibility, mechanical properties, bioactive materialaffinity, storage capacity; and combinations thereof. An organicallymodified silane can be such an agent. By varying the properties of thesol-gel composition, different bioactive material delivery release ratesand profiles can be achieved for various bioactive materials. Forexample, a bioactive material can be released with first order or secondorder kinetics. Delivery can begin upon deployment of the bioactivematerial delivery device, or at a particular time after implantation,and can increase rapidly from zero to a maximal rate over a short periodof time, for example less than an about 5 minutes. Such maximal deliverycan continue for a predetermined period until the delivery rate suddenlydrops. In the field of sustained-release bioactive material delivery itis generally considered desirable to avoid a large bioactive materialdelivery “burst” wherein the majority of the bioactive material isdelivered in a short amount of time. However in some cases the deliveryof a “burst” of bioactive material is highly desirable such as a PCTA orPTA drug coated balloon whose residence time in the treatment area isshort lived. The methods of the present disclosure that allow forincorporation of bioactive material into the forming sol-gel compositioncan be used to tailor the release kinetics. Embodiments adoptingtreating the surface and/or channels of the sol-gel composition with anorganically modified silane can also be used to either speed up or slowthe rate of drug elution. In accordance with the present disclosurethen, a variety of parameters can be adjusted to produce numerousvariations in delivery profiles depending on what is desirable for aparticular bioactive material/disease/patient combination.

The expandable member according to the present disclosure can be aballoon or a basket. The expandable member can be in association with afixed wire system. The basket can be self-expanding or manuallyexpanding. In another embodiment, the basket comprises a material thatcomprises a shape memory metal, shape memory metal alloy, or asuperelastic material. In another embodiment, the material is nickeltitanium. Superelastic materials possess superelasticity which is animpermanent response to relatively high stress caused by a phasetransformation between the austenitic and martensitic phases. Whenmechanically loaded, a superelastic alloy deforms reversibly to veryhigh strains by the creation of a stress-induced phase. When the load isremoved, the new phase becomes unstable and the material regains itsoriginal shape. Alternatively, the basket comprises a metal, polymer,ceramic, or other blends or combinations thereof. The term “basket” canalso refer to a cage.

In another embodiment, the balloon can be a cutting balloon. A cuttingballoon has a special balloon tip with small blades which are activatedwhen the balloon is inflated.

The term “bioactive material(s)” as used herein refers to any organic,inorganic, or living agent that is biologically active or relevant. Forexample, a bioactive material can be a protein, a polypeptide, apolysaccharide (e.g. heparin), an oligosaccharide, a mono- ordisaccharide, an organic compound, an organometallic compound, or aninorganic compound. It can include a biologically active molecule suchas a hormone, a growth factor, a growth factor-producing virus, a growthfactor inhibitor, a growth factor receptor, an anti-inflammatory agent,an antimetabolite, an integrin blocker, or a complete or partialfunctional insense or antisense gene. It can also include a man-madeparticle or material, which carries a biologically relevant or activematerial. An example is a nanoparticle comprising a core with a drug anda coating on the core. Such nanoparticles can be post-loaded into poresor co-deposited with metal ions.

Bioactive materials also can include drugs such as chemical orbiological compounds that can have a therapeutic effect on a biologicalorganism. Bioactive materials include those that are especially usefulfor long-term therapy such as hormonal treatment. Examples include drugsfor contraception and hormone replacement therapy, and for the treatmentof diseases such as osteoporosis, cancer, epilepsy, Parkinson's diseaseand pain. Suitable biological materials can include, without limitation,an anti-restenotic agent, an anti-inflammatory agent, an HMG-CoAreductase inhibitor, an antimicrobial agent, an antineoplastic agent, anangiogenic agent, an anti-angiogenic agent, a thrombolytic agent, anantihypertensive agent, an anti-arrhythmic agent, a calcium channelblocker, a cholesterol-lowering agent, a psychoactive agent, ananti-depressive agent, an anti-seizure agent, a contraceptive, ananalgesic, a bone growth factor, a bone remodeling factor, aneurotransmitter, a nucleic acid, an opiate antagonist and combinationsthereof. Additional bioactive materials include, without limitation,paclitaxel, rampamycin, everolimus, tacrolimus, sirolimus, des-aspartateangiotensin I, nitric oxide, apocynin, gamma-tocopheryl, pleiotrophin,estradiol, aspirin, statin, atorvastatin, cerivastatin, fluvastatin,lovastatin, pravastatin, rosuvastatin, simvastatin, and combinationsthereof.

Bioactive materials also can include precursor materials that exhibitthe relevant biological activity after being metabolized, broken-down(e.g. cleaving molecular components), or otherwise processed andmodified within the body. These can include such precursor materialsthat might otherwise be considered relatively biologically inert orotherwise not effective for a particular result related to the medicalcondition to be treated prior to such modification.

Combinations, blends, or other preparations of any of the foregoingexamples can be made and still be considered bioactive materials withinthe intended meaning herein. Aspects of the present invention directedtoward bioactive materials can include any or all of the foregoingexamples.

There are various ways to apply a bioactive active material to theexpandable members including balloons of the present drug elutingdevices. These methods include spraying or dip coating. Morespecifically, application methods include electrospinning, sol spinning,or electrostatic spraying. Dip coating could include rotation of anexpandable member such as a balloon. The balloon can be held above asolution containing a bioactive material and can be parallel to thesurface. The balloon can be partially submerged such that it rotates aportion of the balloon to give it time to dry before it return to thesolution on the next rotation. Dip coating can also include verticaldipping. The teachings of U.S. Pat. No. 6,764,690 are hereinincorporated by reference in its entirety. U.S. Pat. No. 6,764,690generally teaches spraying drying particles onto a surface. In addition,the bioactive materials may be applied by vapor phase deposition.

In another embodiment, the coating on the expandable member of thepresent drug eluting expandable devices may comprise two more layers,each layer comprising an adjustable matrix composition and a bioactivematerial. In another embodiment, the adjustable matrix is a sol gelmaterial. In another embodiment, the two or more layers of the coatingare different from each other.

Contrast media is any substance that is used to enhance the visibilityof structures or fluids within the body. An example of this is the useof a radiopaque substance during an x-ray exam to highlight featuresthat would otherwise be less distinguishable from nearby tissue. Thecontrast can either be positive or negative. Positive contrast media hasa higher attenuation density than the surrounding tissue. This meansthat the contrast looks more opaque than the surrounding tissue whenseen on an x-ray. Negative contrast media has a lower attenuationdensity than the surrounding tissue. This means that the contrast looksless opaque than the body. Negative contrast is generally found as agas. Contrast can be used to produce images of almost any hollowstructure in the body.

In another embodiment, the coating(s) or the layer(s) on the expandablemember of the present drug eluting devices may be non-uniform. Withoutlimitation, they may be contiguous or non-contiguous. Withoutlimitation, they may be in the form of dots or stripes.

In another embodiment, the expandable member of the present drug elutingdevices can comprise a porous or non-porous material. In anotherembodiment, the expandable member comprises a polymer. Alternatively,the polymer may comprise polyamide, polyolefin, polyethylene, polyester,polyurethane, elastomer, thermoplastic elastormer, nylon elastomer,nylon, nylon blends, copolyamide block ether, polyether block amides(PEBAX), polyethylene terephthalate (PET), polytetrafluoroethylene(PTFE), expanded polytetrafluoroethylene (ePTFE), latex, or silicone; orblends or combinations thereof.

FIG. 1 depicts a drug eluting medical device having an expandable memberin the compressed state which can be self or manually expanded. Theexpandable ribs are in the compressed state 1. A flexible tip 2 is shownwhich can be associated with a guide wire or an over-the-wire typedevice. FIG. 2 depicts a drug eluting medical device having expandableribs 3 which are shown in their expanded state. For a manual expansiondesign, the center component 4 can act as a pull wire to activate theexpansion of the ribs. FIG. 3 depicts a drug eluting device havingexpandable ribs which are self expanding. When the ribs are selfexpanded, a sheath 5 could be retracted to allow the ribs 3 to expand.The ribs can be coated with bioactive materials. FIG. 3 shows four ribsfor the expandable member. However, the number of ribs can be greaterthan four in various embodiments. FIG. 4 depicts a drug eluting medicaldevice with twelve expandable ribs 3 in their expanded state. The ribscan be manually or self-expanded. The ribs can be coated with bioactivematerial. The ribs of FIGS. 1-4 can be a mesh, or weave, or can befilaments at various angles, unparallel to each other and can be ofvarious shapes, widths, and thicknesses.

FIG. 5 shows a drug eluting medical device with a balloon having acoating on its surface 6. FIG. 6 depicts another drug eluting medicaldevice with a balloon having coating on its working length (shown byshading). In this embodiment, the coating is on the middle cylindricalportion which would be in contact with a vessel when expanded. FIG. 7depicts a drug eluting medical device which allows for perfusion. Thearrows show movement of blood during deployment. FIG. 8 depicts a drugeluting medical device having an expandable member in association with afixed wire 7 system, wherein the wire component is integrated with theexpandable member device.

FIGS. 9A-9D depict substrates with coatings. In FIG. 9A the drug matrix8 is shown which has been applied to a substrate 9. FIG. 9B shows anadditional layer which is a tie layer 10. FIG. 9C shows yet anotheradditional layer which is a top layer 11. FIG. 9D shows the tie layer10, drug matrix 8, and a top layer 11 on a substrate 9.

FIGS. 10A and 10B depict substrates with coatings and layers which areirregular or non-uniform. 12 and 14 are drug matrix on the substrate 13.

Perfusion as used herein permits blood flow through the drug elutingexpandable device from the proximal to the distal end during deployment.This reduces the risk of ischemic events. When the expandable member isa basket, there would be natural perfusion through the openings in thebasket. When the expandable member is a balloon which can cause completeocclusion when deployed, openings may be necessary to allow blood flow.

Another embodiment of the present disclosure relates to a medical systemcomprising a stent and a drug eluting device comprising an expandablemember and at least one coating on the expandable member comprising atleast one layer, wherein the at least one layer of the at least onecoating comprises an adjustable matrix composition comprising a sol gelmaterial and a bioactive material. Alternatively, the stent can be abare metal stent or a drug eluting stent. A stent generally is a tubethat is inserted into a natural conduit of the body to prevent orcounteract a disease-induced localized flow constriction. A bare metalstent is made of metal and generally does not elute drug. A drug-elutingstent is a stent placed typically into narrowed, diseased arteries thatslowly releases a drug to block cell proliferation. This preventsscar-tissue-like growth that, together with clots (thrombus), couldotherwise block the stented artery, a process called restenosis. Inanother embodiment, the medical system allows for perfusion duringdeployment. In another embodiment the medical system further comprises adelivery catheter. A catheter is a tube that can be inserted into a bodycavity, duct or vessel. Catheters thereby allow drainage or injection offluids or access by surgical instruments. A delivery catheter allows fordelivery of medical equipment. A delivery catheter herein can be used todeliver the present medical system comprising a stent and a drug elutingdevice. Or it can be used to delivery only a drug eluting device. Inanother embodiment, the drug eluting stent contains the same bioactivematerial as that of the drug eluting device. Or the drug eluting stentcan contain a different bioactive material from that of the drug elutingdevice.

Another embodiment of the present disclosure relates to a drug elutingdevice comprising a balloon and at least one coating on the ballooncomprising at least one layer, wherein the at least one layer of the atleast one coating comprises a bioactive material, wherein the deviceallows for perfusion during deployment. In another embodiment, thecoating can further comprise of contrast media. In another embodiment,the coating further comprises a sol gel material. In another embodiment,the coating is non-uniform. Alternatively, the coating can be in theform of dots or stripes.

In another embodiment, the drug eluting device further comprises amultilumen tubular member comprising two or more lumens, the multilumentubular member comprising a proximal end and a distal end extendingthrough a balloon cavity defined by the balloon. In one embodiment, themultilumen tubular member is a bulilumen tubular member comprising atleast one side opening arranged in the bilumen tubular member locatedboth distal and proximal of the balloon and in fluid communication withone another via a first lumen in the bilumen tubular member, the firstlumen extending from the proximal end of the bilumen tubular memberthrough the tubular member to an end hole distal of the balloon; and thesecond lumen is provided for receiving a pressure fluid for inflatingthe balloon. One of ordinary skill in the art is directed to theteachings of U.S. Pat. No. 5,295,961 contents of which are hereinincorporated by reference in its entirety. U.S. Pat. No. 5,295,961offers a general teaching of a catheter system for mechanical dilatationof coronary stenoses.

In another embodiment, the drug eluting device further comprises anaxially elongate catheter shaft, constructed and arranged for insertioninto a distal body lumen, said catheter shaft having an inflationconduit extending axially therethrough; the balloon secured to saidcatheter shaft, the balloon in fluid communication with the inflationconduit and outwardly radially expandable to a preselected configurationin response to inflation thereof. In one embodiment, the balloon ismulti-lobed. One of ordinary skill in the art is directed to theteachings of U.S. Pat. No. 4,983,167 contents of which are hereinincorporated by reference in its entirety. U.S. Pat. No. 4,983,167offers a general teaching of a catheter system which provides a path forconducting blood past a stenosis and inflated balloons (perfusion). Inanother embodiment, the balloon is multi-lobed.

In another embodiment, the drug eluting device further comprises aninflatable member having generally a helically coiled portion, thehelically coiled portion being inflatable from a deflated configurationto an inflated, configuration defining a generally open lumen. One ofordinary skill in the art is directed to the teachings of U.S. Pat. No.5,181,911 contents of which are herein incorporated by reference in itsentirety. U.S. Pat. No. 5,181,911 offers a general teaching of a helicalballoon catheter which allows for perfusion.

Another embodiment of the present disclosure relates to a method oftreating stenosis or restenosis or in-stent restenosis comprisingdeploying in a subject a drug eluting device comprising an expandablemember and at least one coating on the expandable member comprising atleast one layer, wherein the at least one layer of the at least onecoating comprises an adjustable matrix composition comprising a sol gelmaterial and a bioactive material. In another embodiment, the deviceallows for perfusion during deployment.

Another embodiment of the present disclosure relates to a method oftreating stenosis or restenosis or in-stent restenosis comprisingdeploying in a subject a drug eluting device comprising an expandablemember balloon and at least one coating on the device comprising atleast one layer, wherein the at least one layer of the at least onecoating comprises a bioactive material and a contrast media, wherein thedevice allows for perfusion during deployment. In another embodiment,the expandable member is a balloon and the at least one coating isdeposited on and adhered to the balloon.

EXAMPLES Example 1: Coating of an Expanded Balloon with a PaclitaxelContaining Sol-Gel Matrix

A solution containing 0.2M of TEOS in a mixture of water and ethanol washydrolyzed for 3 hours at pH 3. Paclitaxel was then added to the silanebased solution such that the final concentration of drug was 5 mg/ml.This solution was then sprayed at a flow rate of 40 μl/min via anultrasonic nozzle (operating at 120 KHz) onto a balloon (3.25 mm×19 mm)which in turn was moving at a predefined lateral speed (10 mm/second)and rotation rate (3 Hz) through the spray plume.

The balloon was coated by moving the balloon back and forth through theultrasonically generated spray plume a total of 5 times (referred to as‘passes’). A ‘rest period’ of 90-120 seconds was included betweensuccessive passes in order to allow the matrix to dry and in turnpromote additional cross-linking within the sol-gel.

At this time the balloon was allowed to dry for 16-24 hours beforeevaluating the elution characteristics of the encapsulated drug. Theballoon was placed in different 1 ml aliquots of PBS (Phosphate BufferedSaline) for a series of defined times in order to generate theappropriate elution profile.

The aliquots of PBS were then analyzed by HPLC to establish paclitaxelconcentrations in solution at each time point. The data is presented inFIG. 14.

A series of optical photographs and SEM images were also collected priorto performing the elution analysis in order to evaluate coating adhesionand integrity of the coating. A FEI XL-30 SEM was used to acquire theimages shown in FIGS. 11A and 11B. The following parameters were used toacquire the SEM images: accelerating voltage=2 kV, Current=2 mA, workingdistance=10 mm to 30 mm.

Example 2: Coating of an Expanded Balloon with a Cerivastatin-ContainingSol-Gel Matrix

A solution containing 20% isobutyltriethoxysilane and 80% TEOS (for acombined total concentration of 0.2M) in a mixture of water and ethanolwas hydrolyzed for 3 hours at pH 3. Cerivastatin was then added to thesilane based solution such that the final concentration of drug was 5mg/ml. This solution was then sprayed at a flow rate of 40 μl/min via anultrasonic nozzle (operating at 120 KHz) onto a balloon (3.25 mm×19 mm)which in turn was moving at a predefined lateral speed (10 mm/second)and rotation rate (3 Hz) through the spray plume.

The balloon was coated by moving the balloon back and forth through theultrasonically generated spray plume a total of 5 times. A ‘rest period’of 90-120 seconds was included between successive passes in order toallow the matrix to dry and in turn promote additional cross-linkingwithin the sol-gel. This procedure was repeated with different balloons(10 and 20 times respectively) to include variable numbers of passes andhence therefore variable quantities of drug within the matrix (and henceon the balloon).

At this point the balloon was allowed to dry for 16-24 hours beforeevaluating the elution characteristics of the encapsulated drug. Theballoon was placed in different 1 ml aliquots of PBS for a series oftimes in order to generate the appropriate elution profile.

The aliquots of PBS were then analyzed by HPLC to establish cerivastatinconcentrations in solution at each time point. The data is presentedbelow in FIG. 15.

A series of optical photographs and SEM images were also collected priorto performing the elution analysis in order to evaluate coating adhesionand integrity of the coating. A FEI XL-30 SEM was used to acquire theimages shown in FIGS. 12 and 13. The following parameters were used toacquire these images: accelerating voltage=2 kV, Current=2 mA, workingdistance=10 mm to 30 mm.

Example 3: Coating of an Expanded Balloon with a Paclitaxel ContainingSol-Gel Matrix

A solution containing 10% isobutyltriethoxysilane and 90% TEOS (for acombined total concentration of 0.2M) in a mixture of water and ethanolwas hydrolyzed for 3 hours at pH 3. Paclitaxel was then added to thesilane based solution such that the final concentration of drug was 12mg/ml. This solution was then sprayed at a flow rate of 40 μl/min via anultrasonic nozzle (operating at 120 KHz) onto a balloon (3.25 mm×19 mm)which in turn was moving at a predefined lateral speed (10 mm/second)and rotation rate (3 Hz) through the spray plume.

The balloon was coated by moving the balloon back and forth through theultrasonically generated spray plume a total of 5 times. A ‘rest period’of 90-120 seconds was included between successive passes in order toallow the matrix to dry and in turn promote additional cross-linkingwithin the sol-gel. This procedure was repeated with another balloon atotal of 10 times such that twice as much drug was placed on the balloonwithin the sol-gel based matrix.

At this time the balloon was allowed to dry for 16-24 hours beforeevaluating the elution characteristics of the encapsulated drug. Theballoon was placed in different 1 ml aliquots of PBS for a series ofdefined times in order to generate the appropriate elution profile.

The aliquots of PBS were then analyzed by HPLC to establish paclitaxelconcentrations in solution at each time point. The data is presentedbelow in FIG. 16.

Example 4: Coating of an Expanded Balloon with a Cerivastatin ContainingSol-Gel Matrix

A solution containing 20% isobutyltriethoxysilane and 80% TEOS (for acombined total concentration of 0.2M) in a mixture of water and ethanolwas hydrolyzed for 3 hours at pH 3. Cerivastatin was then added to thesilane based solution such that the final concentration of drug waseither 8.5 mg/ml or 12.4 mg/ml. These solutions were then sprayed at aflow rate of 40 μl/min via an ultrasonic nozzle (operating at 120 KHz)onto a balloon (3.25 mm×19 mm) which in turn was moving at a predefinedlateral speed (10 mm/second) and rotation rate (3 Hz) through the sprayplume. In using this approach, the quantity of drug contained within aset amount of matrix material was varied. This, in turn, allows the userto vary the amount of drug that elutes from the matrix within a settime.

The balloon was coated by moving the balloon back and forth through theultrasonically generated spray plume a total of 5 times. A ‘rest period’of 90-120 seconds was included between successive passes in order toallow the matrix to dry and in turn promote additional cross-linkingwithin the sol-gel.

At this point the balloon was allowed to dry for 16-24 hours beforeevaluating the elution characteristics of the encapsulated drug. Theballoon was placed in different 1 ml aliquots of PBS for a series oftimes in order to generate the appropriate elution profile.

The aliquots of PBS were then analyzed by HPLC to establish cerivastatinconcentrations in solution at each time point, for each variable set ofpasses. The data is presented below in FIG. 17.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should at least be construed in light of thenumber of reported significant digits and by applying ordinary roundingtechniques. Notwithstanding that the numerical ranges and parameterssetting forth the broad scope of the invention are approximations, thenumerical values set forth in the specific examples are reported asprecisely as possible. Any numerical value, however, inherently containscertain errors necessarily resulting from the standard deviation foundin their respective testing measurements.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.Recitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is deemedto contain the group as modified thus fulfilling the written descriptionof all Markush groups used in the appended claims.

Certain embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on these described embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventor expects skilled artisans to employ suchvariations as appropriate, and the inventors intend for the invention tobe practiced otherwise than specifically described herein. Accordingly,this invention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

Furthermore, numerous references have been made to patents and printedpublications throughout this specification. Each of the above-citedreferences and printed publications are individually incorporated hereinby reference in their entirety.

In closing, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

1.-47. (canceled)
 48. A drug eluting device comprising an expandablemember and at least one coating on said expandable member comprising atleast one layer, wherein said at least one layer of said at least onecoating comprises an adjustable matrix composition comprising a sol gelmaterial and a bioactive material, wherein the expandable member is abasket.
 49. The drug eluting device of claim 48, wherein said basketcomprises a material that comprises a shape memory metal, shape memorymetal alloy, or a superelastic material.
 50. The drug eluting device ofclaim 49, wherein the material is nickel titanium.
 51. The drug elutingdevice of claim 48, wherein the basket is self-expanding.
 52. The drugeluting device of claim 48, wherein the basket is manually expanding.53. The drug eluting device of claim 48, wherein the basket comprises ametal, polymer, ceramic or other blends or combinations thereof.
 54. Thedrug eluting device of claim 48, wherein the bioactive materialcomprises at least one of an anti-restenotic agent, an anti-inflammatoryagent, an HMG-CoA reductase inhibitor, an antimicrobial agent, anantineoplastic agent, an angiogenic agent, an anti-angiogenic agent, athrombolytic agent, an antihypertensive agent, an anti-arrhythmic agent,a calcium channel blocker, a cholesterol-lowering agent, a psychoactiveagent, an anti-depressive agent, an anti-seizure agent, a contraceptive,an analgesic, a bone growth factor, a bone remodeling factor, aneurotransmitter, a nucleic acid, an opiate antagonist; and combinationsthereof.
 55. The drug eluting device of claim 48, wherein said coatingcomprises two or more layers, each layer comprising an adjustable matrixcomposition and a bioactive material.
 56. The drug eluting device ofclaim 55, wherein at least one layer comprises a sol gel material. 57.The drug eluting device of claim 55, wherein said two or more layers aredifferent from each other.
 58. The drug eluting device of claim 55,wherein the coating further comprises a contrast media.